Transcript Treatment of Ovarian Cancer 21st Century and Beyond

Treatment of Ovarian Cancer
21st Century and Beyond
Judith
Wolf
Judith
K. K.
Wolf,
MD
Professor
• Department of Gynecologic Oncology • University
Professor
of Texas M.D. Anderson Cancer Center • Houston, TX
Gynecologic Oncology
Ovarian Cancer: 2010
• 1/71 lifetime risk1
• 5-year survival rates (by year of
diagnosis)2
– 1990-1992 42.5%
– 1993-1995 43.5%
– 1996-2003 45%
• Mortality relatively unchanged but
statistically significant improvement in
5-year survival rates
1. SEER (Surveillance, Epidemiology, and End Results) Program Web site.
http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007.
2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007.
Ovarian Cancer Staging
Stage I - Limited to ovaries
A. Unilateral ovary
B. Bilateral ovaries
C. Positive cytology
Stage II - Limited to pelvis
A. Extends to uterus or tubes
B. other pelvic organs
C. Positive cytology
Stage III – Spread to upper abdomen or regional lymph nodes
A. Microscopic spread
B. Macroscopic < 2 cm
C. Macroscopic > 2 cm
Stage IV - Spread outside peritoneum, pleura or parenchymal
liver metastases
Ovarian Cancer
FIGO Staging System
Stage
Description
Incidence
Survival
20%
73%
I
Confined to ovaries
II
Confined to pelvis
5%
45%
III
Confined to abdomen/ 58%
lymph nodes
21%
IV
Distant metastases
<5%
17%
Jelic S, et al. Program and abstracts of the 27th Congress of the European
Society for Medical Oncology; 2002; Nice, France.
Mocharnuk R. Medscape Web site.
http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007.
FIGO = International
Federation of Gynecology
and Obstetrics
Ovarian Cancer Surgical
Debulking and Staging
Exploration
Biopsies
(Staging)
TAH/
BSO
Washings/
Ascites
(Staging)
TAH = total abdominal hysterectomy
BSO = bilateral salphingo-oophorectomy
Goals (Debulking)
• Assessment of extent of disease
• Optimal tumor reduction
First-line Therapy –
Standard Treatment Options
Surgery with maximum
cytoreduction effort <1cm
residual disease
Platinum + Taxane Chemotherapy
(Carboplatin + Paclitaxel)
Chemotherapy
• Standard front-line chemotherapy in the
US today is carboplatin, AUC 6 to 7.5,
paclitaxel 175 mg/m2 every 21 days for
6 cycles
• Result of several studies over last decade
– GOG 1111 and OV 102 - paclitaxel/cisplatin
vs cyclophosphamide/cisplatin
– GOG 1583 and AGO OVAR-34 - carboplatin
instead of cisplatin
1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6.
2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708.
3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200.
4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329.
GOG = Gynecologic Oncology Group
AGO = Arbeitsgemeinschaft
Gynaekologische Onkologie
The Role of Paclitaxel in First-line
Therapy for Ovarian Carcinoma
Study
# Pts
377
GOG
1321 III suboptimal-IV
Median PFS
(mo)
Median OS
(mo)
Cisplatin/
Paclitaxel (24 h) x 6
14.1
26.3
Cisplatin 100 mg/m2 x 6
16.4
10.8
17.3
30.2
25.9
36.1
16.1
35.4
Regimen
Paclitaxel 200 mg/m2 (24 h)*
ICON
32
2074
I-IV
*CR/PR rates on paclitaxel
monotherapy (42%) vs cisplatin
regimens (67%), P <.001
Carboplatin/
Paclitaxel (3 h)
Carboplatin or CAP
CAP = cyclophosphamide, doxorubicin, cisplatin
GOG = Gynecologic Oncology Group
ICON = International Collaborative Ovarian Neoplasm Group
OS = overall survival
PFS = progression-free survival
1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115.
2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515.
The Schedule of Paclitaxel in First-line
Therapy for Ovarian Carcinoma
Study
# Pts
GOG
1581
792
III optimal
Regimen
Median PFS (mo)
Median OS (mo)
Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2 (24 h)
19.4
48.8
Carboplatin AUC 7.5
Paclitaxel 175 mg/m2 (3 h) *
20.7
56.7
* RR progression 0.88 (95% CI) and
RR death 0.86 (95% CI)
AGO2
798
IIB-IV
HR =0.86
(99% CI)
Cisplatin 75 mg/m2
Paclitaxel 185 mg/m2 (24 h)
19.1
44.1
Carboplatin AUC 6
Paclitaxel 185 mg/m2 (3 h)
17.2
43.3
HR = 1.050
(95% CI)
HR =1.045
(95% CI)
More toxicity with the cisplatin regimens
1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155.
2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329.
AGO = Arbeitsgemeinschaft
Gynaekologische Onkologie
CI = confidence interval
GOG = Gynecologic Oncology Group
HR = hazard ratio; OS = overall survival
PFS = progression-free survival
RR = relative risk
SCOTROC: Trial
• Ovarian cancer
stage Ic-IV
• Primary
peritoneal cancer
• N = 1077
R
A
N
D
O
M
I
Z
E
Carboplatin AUC 5,
+ docetaxel 75 mg/m2 (1 h)
Q3W x 6
Carboplatin AUC 5,
+ paclitaxel 175 mg/m2 (3 h)
Q3W x 6
SCOTROC = Scottish Randomized Trial in Ovarian Cancer
Q3W = once every 3 weeks
Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
SCOTROC: Results
Parameter
DC
PC
Response (standard)
59%
60%
Response (CA-125)
76%
77%
Progression-free survival
15 mos
14.8 mos
Overall survival at 24 months
64%
69%
DC = docetaxel-carboplatin
PC = paclitaxel-carboplatin
SCOTROC = Scottish Randomized Trial in Ovarian Cancer
Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
SCOTROC: Conclusion
• PC vs DC: PC the Standard
–
Overall toxicity clearly favors paclitaxel regimen
for all except neurotoxicity and arthralgia/myalgia
–
Differences in neurotoxicity related to taxane in
each regimen should be reversible
–
Myelotoxicity worse with docetaxel and prevents
use of what may be optimal dose of carboplatin
–
Paclitaxel/carboplatin remains the standard of
care in order to maximize efficacy, minimize lifethreatening toxicity
Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.
DC = docetaxel-carboplatin
PC = paclitaxel-carboplatin
GOG 182-ICON5
International Study for Stage III/IV
Regimen I (control)
Paclitaxel 175 mg/m2 IV (3 h)
Carboplatin AUC 6 IV
d1
d1
Regimen II (triplet A)
Paclitaxel 135 mg/m2 IV (3 h) d 1
Carboplatin AUC 5 IV
d1
Gemcitabine 800 mg/m2/d IV
d 1, 8
Randomization
• All patients
• Equal proportions on
each regimen
• Primary end points:
PFS, OS, RR
Regimen III (triplet B)
Paclitaxel 135 mg/m2 IV (3 h)
Carboplatin AUC 5 IV
Doxil 30 mg/m2 IV
Every other cycle
Regimens I, II, and III: 8 cycles,
21-d cycle interval
Regimens IV and V: 4 cycles,
21-d cycle interval
d1
d1
d1
Regimen IV (sequential module A)
Carboplatin AUC 5 IV
d3
Topotecan 1.25 mg/m2/d IV
d 1-3
Regimen IV (sequential module B)
Paclitaxel 175 mg/m2 IV (3 h) d 1
Carboplatin AUC 6 IV
d1
Regimen V (sequential module A)
Carboplatin AUC 6 IV
d8
Gemcitabine 1000 mg/m2/d IV d 1, 8
Regimen V (sequential module B)
Paclitaxel 175 mg/m2 IV (3 h) d 1
Carboplatin AUC 6 IV
d1
Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.
GOG = Gynecologic Oncology Group; ICON = International
Collaborative Ovarian Neoplasm Group; OS = overall survival;
PFS = progression-free survival; RR = response rate
GOG0182-ICON5: Progression-Free
Survival
Median PFS and HR (95% CI)
16.1
16.4
16.4
15.3
15.4
1.000
0.990
0.998
1.094
1.052
(0.884-1.107)
(0.891-1.117)
(0.979-1.224)
(0.940-1.176)
Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.
C = carboplatin
D = pegylated liposomal doxorubicin
G = gemcitabine
P = paclitaxel; PFS = progression-free survival
T = topotecan
GOG0182-ICON5: Overall Survival
Median OS and HR (95% CI)
40.0
40.4
42.8
39.1
40.2
Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.
1.000
0.978
0.972
1.068
1.035
(0.838-1.141)
(0.832-1.136)
(0.918-1.244)
(0.888-1.206)
C = carboplatin
D = pegylated lipososomal doxorubicin
G = gemcitabine
P = paclitaxel; 0S = overall survival
T = topotecan
Current GOG Frontline Trial
GOG 218
> Microscopic residual
EOC, PPC cancer
Paclitaxel Paclitaxel
Paclitaxel
Carboplatin Carboplatin Carboplatin
Placebo Bevacizumab Bevacizumab
Placebo
Placebo Bevacizumab
×16 cycles ×16 cycles ×16 cycles
N = 2,000 patients
Survival, PFS primary endpoints
Biologic & QOL endpoints
EOC = epithelial ovarian cancer
FT = fallopian tube
GOG = Gynecologic Oncology Group
PFS = progression-free survival
PPC = primary peritoneal cancer
QOL = quality of life
EORTC-55971
Upfront Debulking Surgery vs
Neoadjuvant Chemotherapy
Stage IIIc or IV Epithelial Ovarian Carcinoma
Cytoreductive Surgery
+
3 Courses Platinum-Based
Chemotherapy
IDS Allowed
Repeat
Chemotherapy
SLS allowed
3 Courses Platinum-Based
Chemotherapy
IDS With
Response or
Stable Disease
Repeat
Chemotherapy
SLS allowed
The EORTC Groups Web site. Gynaecological Cancer Group Active
Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971.
Accessed June 12, 2007.
EORTC = European Organisation for
Research and Treatment of Cancer
IDS = Interval Debulking Surgery
SLS = Second-Look Surgery
GC vs TC Induction Regimens Followed
by T Consolidation: Study Design
Histologic diagnosis and prior resection of
stage IC-IV epithelial ovarian, primary peritoneal,
or fallopian tube carcinoma
Induction GC
Gemcitabine 1000 mg/m2 Days 1, 8
+ Carboplatin AUC 5 Day 1
x 6 cycles every 21 days
Induction TC
Paclitaxel 175 mg/m2 Day 1
+ Carboplatin AUC 6 Day 1
x 6 cycles q 21 days
Clinical CR
Anything other than CR
(PR, SD, PD)
Anything other than CR
(PR, SD, PD)
Elective
T Consolidation Therapy
Paclitaxel 135 mg/m2
every 28 days for 12 cycles
Single-agent crossover
Paclitaxel 175 mg/m2 Day 1
Gordon A, et al. ASCO 2008. Abstract 5536.
Single-agent crossover
Gemcitabine 1000 mg/m2 Days 1, 8
GC vs TC Induction Regimens Followed
by T Consolidation: Response Rates
CR*
Induction
GC
(n = 66)
30 (45.5)
Induction
TC
(n = 58)
26 (44.8)
PR
SD
PD
13 (19.7)
5 (7.6)
6 (9.1)
12 (20.7)
8 (13.8)
4 (6.9)
Data not available
ORR (CR + PR)
12 (18.2)
43 (65.2)
8 (13.8)
38 (65.5)
 .999
DCR (CR + PR + SD)
48 (72.7)
46 (79.3)
.410
Best response, n (%)
Gordon A, et al. ASCO 2008. Abstract 5536.
P
Value
*CR required a normalized CA-125.
GC vs TC Induction Regimens Followed
by T Consolidation: Pt-Based Toxicity
Induction
GC
(n = 219)
Induction
TC
(n = 220)
P Value
88 (40.2)
55 (25.1)
30 (13.6)
10 (4.5)
 .0001
G3/4 anemia
Nonhematologic
 G2 neuropathy
52 (23.7)
20 (9.1)
 .0001
24 (11.0)
43 (19.5)
.0165
G2 alopecia
Platelet transfusion
79 (36.1)
7 (3.2)
110 (50.0)
0 (0)
.0038
.0073
Toxicity, n (%)
Hematologic
G3/4
thrombocytopenia
Gordon A, et al. ASCO 2008. Abstract 5536.
Conventional vs Dose-Dense
TC (NOVEL): Study Design
Ovarian epithelial, primary peritoneal, or
fallopian tube cancer with
FIGO stage II-IV
Stratified by
residual disease ≤ 1 cm vs > 1 cm;
FIGO stage II vs III vs IV;
histology: clear cell/mucinous vs serous/others
Conventional TC (c-TC)
Paclitaxel 180 mg/m2 Day 1 +
Carboplatin AUC 6.0 Day 1
every 21 days for 6-9 cycles
Isonishi S, et al. ASCO 2008. Abstract 5506.
Dose-dense weekly TC (dd-TC)
Paclitaxel 80 mg/m2 Days 1, 8, 15 +
Carboplatin AUC 6.0 Day 1
every 21 days for 6-9 cycles
Conventional vs Dose-Dense TC
(NOVEL): Clinical Responses
Patients, %
Measurable
Objective response
• CR
• PR
NC
PD
NE
c-TC
(n = 135)
53
dd-TC
(n = 147)
56
16
38
31
7
9
20
36
29
3
12
P = .72
Isonishi S, et al. ASCO 2008. Abstract 5506.
Evaluated by WHO criteria
Conventional vs Dose-Dense TC
(NOVEL): PFS
Isonishi S, et al. ASCO 2008. Abstract 5506.
Proportion Surviving
Progression Free
1.0
0.9
dd-TC
c-TC
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
Mos From Randomization
n
Event
Median PFS,
mos
c-TC
319
200
17.2
dd-TC
312
160
28.0
Treatment
42
48
54
P Value
HR
95 %CI
.0015
0.714
0.581-0.879
Ovarian Carcinoma:
Clinical Course
Interval
Cytoreduction
Diagnosis
Symptoms
Chemotherapy #1
Second-Look
Secondary
Cytoreduction
Progression
Consolidation/
Maintenance
Chemo #2
Cure
Staging
Primary cytoreduction
Death
Chemo #3+
Supportive
Care
Goals of Treatment:
Relapsed Ovarian Cancer
• Prolong Survival
• Delay Time to Progression
• Control Disease-Related Symptoms
• Minimize Treatment-Related Symptoms
• Maintain or Improve Quality of Life
Issues Impacting Therapy for
Recurrent Ovarian Cancer
• Treatment-free interval
– Impact of consolidation/maintenance therapy
• Number of prior regimens
– Response to prior therapy
• Toxicity from prior therapy
– Prior use of growth factors
– Transfusion requirements
– Neuropathy
• Volume and site(s) of disease
– Ascites/GI symptoms
– Performance status
Surveillance Options for Ovarian
Cancer Patients in Remission
• Second-look laparotomy
• Physical examination
– Include pelvic examination
• CA-125
• Imaging
– CT scan
– MRI?
– PET scan?
CT = computed tomography
MRI = magnetic resonance imaging
PET = positron emission tomography
Ovarian Cancer:
How is Relapse Defined?
• Continuous rise in CA-125
• CA-125 above 100
• Radiographic recurrence
• Symptomatic recurrence
• Physical examination findings
• Combination of above
When Does Ovarian Cancer Recur?
Population
Optimal St III
Study
Treatment
PFS
GOG 114
IV Carb & Pac, IP Cis
28 mos
GOG 172
IV Pac, IP Cis & Pac
24 mos
GOG 158
IV Pac & Carb
21 mos
GOG 114
IV Pac & Cis
22 mos
GOG 158
IV Pac & Cis
19 mos
GOG 172
IV Pac & Cis
18 mos
Suboptimal III & IV GOG 111
IV Pac & Cis
18 mos
GOG 162
IV Pac Cis
12 mos
GOG 152
IV Pac Cis
11 mos
Stage IC-IV
SCOTROC
Doc Carbo
15 mos
Stage IC-IV
SCOTROC
Pac Carbo
15 mos
All Stage III & IV
GOG 182
IV Pac/Carbo x 8
16 mos
Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel;
GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel
Active Agents in Ovarian Cancer
FDA approved
Altretamine
Carboplatin
Cisplatin
Gemcitabine/
Carboplatin
Paclitaxel
Pegylated liposomal
doxorubicin
Topotecan
Not FDA approved, compendium listed
Chlorambucil
Cyclophosphamide
Docetaxel
Doxorubicin
Epirubicin
Etoposide
5-FU/LV
Gemcitabine
Ifosfamide
Irinotecan
Melphalan
Methotrexate
Thiotepa
Vinorelbine
Not FDA approved, not compendium listed
Aromatase inhibitors
Tamoxifen
Bevacizumab
Pemetrexed
Effect of Platinum-Free Interval
on Response Rate
% Response to Second-line
Platinum Therapy
Platinum-Free
Interval (mos)
Markman
Gore
0-6
Blackledge
10%
15%
29%
20%
63%
30%
94%
30%
17%
7-12
27%
13-18
33%
27%
19-24
>24
59%
57%
Markman M, et al. J Clin Oncol. 1991;9(3):389-393.
Gore ME, et al. Gynecol Oncol. 1990;36:207-211.
Blackledge G, et al. Br J Cancer. 1989;59:650-653.
Non-Platinum
Therapy
Ovarian Cancer at First Relapse
Definition of Sensitivity
P
R 0
3
I
M
A Refractory
R
Y
T
R
E
A
T
M
E
N
T
6
12
18
24
Months
Resistant
Sensitive
“Very Sensitive”
Defined as measurable recurrence, not biochemical (CA-125) recurrence
ICON 4 Schema
• Relapsed ovarian or
primary
• Peritoneal requiring
chemotherapy
• Previous platinum-based
chemotherapy
Prior chemotherapy
• Carboplatin (31%)
• Paclitaxel/platinum (40%)
• Other (30%)
R
A
N
D
O
M
I
Z
E
Conventional
platinum-based
chemotherapy
Paclitaxel plus
platinum
chemotherapy
TFI > 12 months for 75%
Parmar MK, et al. Lancet. 2003;361:2099-2106.
ICON = International Collaborative Ovarian Neoplasm Group
TFI = treatment-free interval
ICON 4 Response
CR or PR
Plat
(n = 128)
Pac-Plat
(n = 119)
54%
66%
(Difference of 12%; 95% CI -0.1% to 24%; p=0.06)
Parmar MK, et al. Lancet. 2003;361:2099-2106.
CR = complete response; ICON = International Collaborative
Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum;
PR = partial response;
Ovarian Carcinoma:
ICON 4 Progression-Free Survival
Proportion alive and
progression-free
1.0
0.9
Hazard ratio = 0.76
(95% CI 0.66 - 0.89; p < 0.001)
Absolute difference at 1 year = 10%
(40% to 50%; 95% CI 4% to 15%)
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Pac-Plat
Plat
0.1
0.0
0
1
2
3
4
Years from randomization
Patients at risk
Pac-Plat
392
Plat
410
179
157
Parmar MK, et al. Lancet. 2003;361:2099-2106.
52
45
25
17
17
7
ICON = International Collaborative Ovarian Neoplasm Group;
Pac = paclitaxel; Plat = platinum
ICON 4: Overall Survival
Hazard ratio = 0.82
(95% CI 0.69 - 0.97; p = 0.023)
Absolute difference 2 years = 7%
(50% to 57%; 95% CI 1% to 12%)
1.0
Proportion
alive
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Pac-Plat
Plat
0.1
0.0
0
Patients at risk
Pac-Plat
392
410
Plat
1
2
3
4
Years from randomization
306
295
Parmar MK, et al. Lancet. 2003;361:2099-2106.
167
150
96
68
43
33
ICON = International Collaborative Ovarian Neoplasm Group;
Pac = paclitaxel; Plat = platinum
Gem/Carbo vs Carbo: Design
• Recurrent ovarian cancer
• 6+ months after platinum
• Strata
– PFI (6 - 12, >12 months)
– 1st-line therapy (platinum
± paclitaxel)
– Measurable vs evaluable
• Primary endpoint = PFS
Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707.
R
A
N
D
O
M
I
Z
E
Gemcitabine 1,000 mg/m2
days 1 + 8 Plus
Carboplatin AUC 4 day 1
every 21 days × 6
Carboplatin AUC 5 day 1
every 21 days × 6
Carbo = carboplatin
Gem = gemcitabine
PFI = progression-free interval
PFS = progression-free survival
AGO OVAR 2.5 Primary Endpoint:
Progression-Free Survival
1.0
Progression-Free Probability
Log-rank p-value = 0.0038
Unadjusted HR = 0.72 (0.57 to 0.90)
0.8
Adjusted HR* = 0.71 (0.57 to 0.89)
0.6
GCb: median = 8.6 mo
Censoring: 12.4%
0.4
GCb Arm (N=178)
Cb Arm (N=178)
0.2
Cb: median = 5.8 mo
Censoring: 12.9%
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
Progression-Free Survival Time (mo)
* Adjusted for PFI, Tumor size
Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
AGO = Arbeitsgemeinschaft Gynaekologische
Onkologie; GCb = gemcitabine; Cb = carboplatin
39
AGO OVAR 2.5 Efficacy Results:
Overall Survival
Proportion Surviving
1.0
0.9
Median = 18.0 mo
Censoring: 18.5%
0.8
GCb Arm (N=178)
Cb Arm (N=178)
0.7
0.6
Log-rank p-value = 0.7349
0.5
Unadjusted HR = 0.96 (0.75 to 1.23)
0.4
Adjusted* HR = 0.92 (0.72 to 1.16)
Median = 17.3 mo
Censoring: 22.5%
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
Months
* Adjusted for PFI, Tumor size and performance status
Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
AGO = Arbeitsgemeinschaft
Gynaekologische Onkologie; GCb = gemcitabine;
Cb = carboplatin
GCIG CALYPSO Trial
Accrual Completed
(Target accrual 864 pts)
PFS 1° endpoint
Ovarian Cancer
Platinum Sens.
Stratify:
< 0.5 cm
> 0.5-2 cm
R
A
N
D
O
M
I
Z
E
PLD
30 mg/m2
Carboplatin AUC = 5
q 28 days x 6
Paclitaxel 175 mg/m2
Carboplatin AUC = 5
q 21 days x 6
GCIG = Gynecologic Cancer Intergroup
PFS = progression-free survival
PLD = pegylated liposomal doxorubicin
Farletuzumab (MORAb-003) in PlatinumSensitive EOC: Study Rationale
• FRA is overexpressed in most EOC; largely
absent from normal tissue
• Binding of MORAb-003 to FRA blocks
phosphorylation by Lyn kinase; mediates FRAexpressing tumor cell killing; suppresses tumor
growth in xenograft models
• Phase I study of single agent MORAb-003
demonstrated no significant adverse effects and
suggested efficacy in platinum-resistant EOC
MORAb-003 in Platinum-Sensitive
EOC: Phase II Study Design
Patients with platinum-sensitive EOC in first relapse
after first remission of 6-18 months duration
with evaluable disease by CA125
(Enrolled N = 58;
eligible n = 54)
Asymptomatic relapse
Single-agent Farletuzumab until
progression
(n = 28)
Symptomatic relapse
Original Carbo/Taxane regimen
+ Farletuzumab for 6 cycles
(n = 26)
Single-agent ORR
Combination ORR
Farletuzumab maintenance
Rx for responders
Compare lengths of first and
second remissions
Armstrong DK, et al. ASCO 2008. Abstract 5500.
MORAb-003-002 Phase II:
Treatment Arms
All arms
 MORAb-003: 100 mg/m2 weekly
– Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2
Combination therapy arm every 21 days x 6 cycles
 Carboplatin: AUC 5-6
 Taxane
– Paclitaxel 175 mg/m2 over 3 hours or
– Docetaxel 75 mg/m2
Armstrong DK, et al. ASCO 2008. Abstract 5500.
Comparison of First vs Second
Remission Length: n = 6
Subject
1st Remission,
Mos
2nd Remission,
Mos
Status
1
8.3
19.5+
Still in remission
2
10.8
19.1+
Still in
remission
3
10.1
15.8+
Still in
remission
4
9.5
9.6+
5
8.2
8.2
Still in
remission
Relapsing
6
6.5
7.8+
Armstrong DK, et al. ASCO 2008. Abstract 5500.
Still in
remission
Data as of May 5, 2008.
MORAb-003-002 Clinical Responses
by RECIST (Combination Therapy)
Best response
• CR: 7.4%
ORR: 70.3%
Patient benefit: 96.3%
• PR: 62.9%
• SD: 25.9%
• PD: 3.7%
• Based on all scans submitted as of December 3, 2007 (~
30%)
• By independent central reader
• MORAb-003 well tolerated; no increase observed in
toxicity profile in combination arm
Armstrong DK, et al. ASCO 2008. Abstract 5500.
Tumor Mass
Secondary
Cytoreduction
• Controversial
• Inconsistent definitions
• Benefit appears confined
to patients likely to
respond to additional
chemo:
• >12 month PFI
• Isolated site of
recurrence
• Disease
completely
resectable
PFI = progression-free interval
Vena Cava
Renal Vein
Kidney
Diaphragm
Kidney
Resected Liver
Ovarian Cancer Secondary
Cytoreduction:
Post-Surgery Survival
Author
Janicke
Segna
Zang
Gadducci
Eisenkop
Munkarah
Scarabelli
Tay
Total/Range
Year
1992
1993
2000
2000
2000
2001
2001
2002
N
30
100
60
30
114
25
148
46
553
Survival
Median
mos
16
16.6
13
21
16.8
26
13-26
TTP
mos
<12
<12
<12
<17.5
<12
<24
<12
<12
Survival
Median
mos
8
8.8
8
15
25
42
12
6
6-42
TTP
mos
>12
>12
>12
>17.5
>36
>24
12-24
>24
Survival
Median
mos (P)
29 (0.002)
22.9 (0.007)
12 (0.02)
25 (0.04)
56.8 (0.005)
57 (NS)
32 (0.001)
39 (0.001)
12-56
TTP = time to progression
GOG 213- PI Robert Coleman
Recurrent ovarian or peritoneal cancer
TFI >6 mos
Surgery
Randomize to
Chemotherapy
YES
No surgery
Surgical
Candidate
?
NO
Carboplatin + Paclitaxel
Carboplatin + Paclitaxel
+ Bevacizumab
+ Bevacizumab Maintenance
GOG = Gynecologic Oncology Group
TFI = treatment-free interval
Effect of Platinum-Free Interval
on Response Rate
% Response to Second-line
Platinum Therapy
Platinum-Free
Interval (mos)
Markman
Gore
0-6
Blackledge
10%
15%
29%
20%
63%
30%
94%
30%
17%
7-12
27%
13-18
33%
27%
19-24
>24
59%
57%
Markman M, et al. J Clin Oncol. 1991;9(3):389-393.
Gore ME, et al. Gynecol Oncol. 1990;36:207-211.
Blackledge G, et al. Br J Cancer. 1989;59:650-653.
Non-Platinum
Therapy
Recent Phase II GOG Studies in
Platinum-Resistant Ovarian Cancer
Study
126-B
126-C
126-D
126-E
126-G
126-H
126-I
126-J
Agents
CDDP & Cyclosporine-A
Hexamethylmelamine
Pyrazoloacridine
PSC833 + paclitaxel
CI-958
Topotecan (24 h)
9-amino-camptothecin
Docetaxel
Bookman MA. Semin Oncol 2002;29(suppl 1):20-31.
Response/comm
3/23 (13%) Inactive
3/30 (10%) Inactive
2/24 (8.4%) Inactive
1/16 (6%) Inactive
1/25 (4%) Inactive
1/25 (4%) Inactive
8/58 (14%) Moderate
13/58 (22%) Active
(post-paclitaxel)
CDDP = c/s-diamminedichloroplatinum (cisplatin)
GOG = gynecologic oncology group
Recent Phase II GOG Studies in
Platinum-Resistant Ovarian Cancer
Study
126-K
126-L
126-M
126-N
126-O
126-P
126-Q
126-R
Agents
Response/comm
Oxaliplatin
1/25 (4%) Inactive
Gemcitabine/CDDP 9/57 (16%) Moderate
Ixabepilone
7/50 (14%) Moderate
Paclitaxel weekly
10/48 (21%) Active
(post-paclitaxel)
Triapine-CDDP
Not Feasible
Paclitaxel & Celecoxib
Closed Early
Pemetrexed
10/48 (21%) Active
Abraxane
Accrual in Progress
Bookman MA. Semin Oncol 2002;29(suppl 1):20-31.
CDDP = c/s-diamminedichloroplatinum (cisplatin)
GOG = gynecologic oncology group
Pemetrexed in Platinum-Resistant
EOC: Phase II GOG Study Schema
Patients with persistent or recurrent platinum-resistant
EOC or primary peritoneal cancer who have failed on
higher priority treatment protocols
Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle;
patients who have received previous radiotherapy will initiate
pemetrexed at level I reduction dose until disease progression or
adverse effect prohibits further therapy
Day
-7
Day Day
-6
-5
Folic Folic Stop
acid, acid NSAID
Vitamin
, folic
B12
acid
Days Day
Day
Day
Day
-4,-3
-2
-1
1
2
Folic Stop Dexamethasone, Chemotherapy, Dexamethasone
dexamethasone
,
acid NSAID,
folic acid
, folic acid
folic acid
folic
acid
Miller DS, et al. ASCO 2008. Abstract 5524.
Phase II GOG Study Evaluation of
Pemetrexed: Clinical Responses
Category
Response
• CR
No. of Cases
Pts, %
1
2.1
• PR
• SD
• Increasing
disease
9
17
18
18.8
35.4*
37.5
• Not evaluable
Total
3
48
6.3
100
Miller DS, et al. ASCO 2008. Abstract 5524.
*1 patient remains on therapy.
Cochrane Review of Tamoxifen for
Relapsed Ovarian Cancer
• 13 studies (11non-randomized series, 1 nonrandomized phase II and 1 randomized trial)
• 59 of 568 women (10.4%) treated with tamoxifen
achieved an objective response (RR)
– RR varied from 0% to 56%
– Stable disease, for variable periods of 4 weeks or
more, in 109 of 356 (30.6%) from 8 studies
– Not enough data to assess duration of RR, survival, or
the effect of tamoxifen on quality of life
• No reliable data from randomized controlled trials
Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034.
RR = response rate
GOG Experience
• GOG 160: Trastuzumab
• GOG 170
Human Interleukin-12 (170B)
Gefitinib (170C)
Bevacizumab (170D)
Imatinib (170E)
Bay 43-9006 (170F)
Lapatinib (170G)
Vorinostat (170H)
Temsirolimus (170I)
Enzastaurin (170J)
Mifepristone (170K)
Insufficiently Active
Too Early
Active
Ongoing GOG Phase II Effort
GOG = Gynecologic Oncology Group
Antiangiogenic Agents in Testing
for Treatment of Ovarian Cancer
Agent
Targets
Ligand binding:
Bevacizumab
VEGF-A
VEGF-Trap
VEGF-A, -B, -C, -D, -E, PIGF-1 and -2
Receptor binding:
Volociximab
51 integrin
IMC-1121B
VEGFR-2
Receptor tyrosine kinase inhibition:
Valatanib
VEGFR-1, -2, -3, PDGFR, and c-kit
Sunitinib
PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3
AMG-706
VEGFR-1, -2, -3, PDGFR, and c-kit
Sorafenib
Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR- 
Non-receptor kinase inhibition:
EGFR = epidermal growth factor receptor;
Temsirolimus, everolimus
mTOR
Mab = monoclonal antibody; mTOR =
Enzastaurin
PKC- 
mammalian target of rapamycin; PDGF-R =
Dasatinib
Src kinase platelet derived growth factor receptor;
PKC-b = protein kinase C-beta;
VEGF = vascular endothelial growth factor
Rationale for Targeting VEGF in
Treatment of Epithelial
Ovarian
Cancer
• Human tumors
– VEGF over-expressed in epithelial ovarian cancers,
associated with
• Ascites formation
• Malignant progression
• Poor prognosis
• Preclinical models of solid tumors
– Anti-VEGF therapy:
• Slowing of tumor progression
• Resolution of malignant effusions
• Synergy with cytotoxic agents
Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345.
Burger RA. J Clin Oncol. 2007;25(20):2902-2908.
VEGF = vascular endothelial growth factor
Agents Targeting the VEGF
Pathway
Anti-VEGF
Antibodies
VEGF
Soluble
VEGFRs
(bevacizumab)
(VEGF-TRAP)
Anti-VEGFR
Antibodies
P
P
P
P
VEGFR-1
P
P
VEGFR-2
Endothelial Cell
Podar K, et al. Blood. 2005;105(4):1383-1395.
P
P
Small-Molecule Inhibitors
VEGF = vascular endothelial growth factor
VEGFR = VEGF receptor
Bevacizumab - Toxicity
• Proteinuria (usually G1 – G2)
• Muco-cutaneous hemorrhage
– Common – G1 epistaxis
– Rare (possibly life-threatening) G2-G4 tumor site hemorrhage
(primarily lung cancer trials)
• Arterial thromboembolism
– Uncommon (3% - 5%)
– Risk factors: age > 65, prior arterial TE
– Risk of venous thromboembolism not increased
• GI perforation – wound healing
– Perforation uncommon (2% - 4% in solid tumor population)
– Wound dehiscence rate 1%
Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345.
Burger RA. J Clin Oncol. 2007;25(20):2902-2908.
G1, G2 = immunoglobulins
GI = gastrointestinal
TE = thromboembolism
Phase II Studies of Bevacizumab
in Ovarian Cancer
Cannistra
2007
Burger
2007
Garcia
2008
Number of Pts
44
62
70
Prior Regimens
2= 52%
3= 48%
1= 34%
2 = 66%
Median = 2
Range 1-3
Response Rate
16% (PRs)
18% (PRs)
3% (CRs)
24% (PRs)
GI Perforations
11%
0%
6%
Arterial
Thromboembolism
7%
0%
4%
Deaths
7%
0%
4%
Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186.
Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171.
Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82.
CR = complete response
GI = gastrointestinal
PR = partial response
GI Perforations with Bevacizumab
in Ovarian Cancer
Study
GI (Gastrointestinal)
Perforations
Burger (GOG 170D)
0/62 (0)
Garcia (ASCO 2005)
2/29 (6.9)
Cannistra (ASCO 2006)
5/44 (11.4)
Wright (ASCO 2006)
4/62 (6.5)
Friberg (ASCO 2006)
2/13 (15.4)
Monk (Gyn Oncol 2006)
1/32 (3.1)
Wright (Cancer 2006)
2/23 (8.7)
Bidus (Gyn Oncol 2006)
0/3 (0)
Penson (ASCO 2006)
0/30
Total
16/298 (5.4%)
Han E, et al. Gynecol Oncol. 2007;105(1):3-6.
GI = gastrointestinal
NCI Registered Phase II Trials:
Anti-VEGF + Cytotoxic
Protocol
Drug
PI
Class
Status
MDA-2006-0329
AVE-0005 - Docetaxel
Receptor
Coleman
Active
NCT00129727*
Bev (+CT**)
MAb
Penson
Active
TEACO*
Bev + Ox/Docetaxel
MAb
Herzog
Active
MCC-105366c
Bev + Docetaxel
MAb
Wenham
Active
ALSSOPR0501
Bev + Paclitaxel ProteinBound
MAb
Schwartzberg
Active
NCT00343044
Bev + Topotecan
MAb
McGonigle
Active
NCT00267696
Bev + Carbo/Gem
MAb
Copeland
Active
AVF3953
Bev + IV Paclitaxel/IP 
Bev
MAb
McMeekin
Active
NCT00418093
Bev + Ox/Gem
MAb
Horowitz
Active
* Front Line
**Carboplatin and Paclitaxel
Bev = bevacizumab; Carbo = carboplatin
Gem = gemcitabine; IP = intraperitoneal
Mab = monoclonal antibody; Ox = Oxaliplatin;
VEGF = vascular endothelial growth factor
NCI Registered Phase II Trials:
VEGF + EGFR Inhibitors
Protocol
NCI
NCT00130520
NCT00520013
Drug
Class
Bev +Erlotinib
MAb
Bev +/Erlotinib
Consolidation
MAb
PI
Status
Friberg
Active
Alberts
Active
Campos
Active
Bev = bevacizumab
EGFR = epidermal growth factor receptor
Mab = monoclonal antibody
VEGF = vascular endothelial growth factor
NCI Registered Phase II Trials:
Other Anti-Angiogenic Agents
Protocol
Drug
GOG 170-J
Enzastaurin
(TKI)
NCT00391118
CT +/[Enzastaurin 
Enzastaurin]
GOG 170-E
Target(s)
PKC -b
Imatinib (TKI)
PDGF-R
NCT00516841
Volociximab
(MAb)
51 Integrin
NCT00479817
AMG 386
(Peptibody)
Angiopoietins
NCT00039585
PI
Status
Usha
Suspended
(Not Listed)
Active
Schilder
Kohn
Completed
Multiple
Active
(Not Listed)
Active
CT = chemotherapy; GOG = gynecologic oncology group;
EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; PDGF-R = platelet derived
growth factor receptor; PKC-b = protein kinase C-beta; TKI = tyrosine kinase inhibitor
Bev + Topotecan in Platinum
Refractory Ovarian Cancer: Study
Design
 Single arm, 2-site phase II trial
PD as defined by
RECIST criteria
Platinum-refractory
OC; recurrence
< 6 mos of platinum
therapy; received
max of 2 previous
chemotherapy
regimens
Bevacizumab
10 mg/kg Days 1, 15
+ Topotecan
4 mg/m2
Days 1, 8, 15 for
28-day cycles
(N = 40)
Treatment
continued until
1 of the
following
events
Excessive toxicity
according to
prespecified criteria
Toxicity requiring
topotecan delay
> 2 weeks or
bevacizumab delay
> 2 months
Topotecan-related
toxicities requiring
> 2 dose reductions
McGonigle KF, et al. ASCO 2008. Abstract 5551.
Patients Surviving (%)
OS: Patients With PlatinumResistant Ovarian Cancer (N = 30)
1.0
Bev + Topotecan
.75
.50
.25
0.0
0
2
4
6
8
10
Time (Mos)
McGonigle KF, et al. ASCO 2008. Abstract 5551.
12
14
16
18
20
PFS in Patients Receiving Bev +
Topotecan by No. of Prior Regimens
Patients Without PD (%)
Patients with 1 previous therapy (n = 16)
1.0
Patients with 2 previous therapies (n = 14)
P = .040 by log rank test
.75
.50
.25
0.0
0
2
4
6
8
10
12
Time (Mos)
McGonigle KF, et al. ASCO 2008. Abstract 5551.
14
16
18
20
Best Response of Bev + Topotecan by
No. of Prior Regimens
No. of Previous
Regimens
Best Response (N =24)
PR or SD
PD
Total
5
9
14
8
2
10
13
11
24
1 previous
chemotherapy
2 previous
chemotherapies
Total
McGonigle KF, et al. ASCO 2008. Abstract 5551.
OS in Patients Receiving Bev +
Topotecan by No. of Prior Regimens
Patients Surviving (%)
1.0
.75
.50
Patients with 1
previous therapy (n = 16)
.25
Patients with 2 previous therapies (n = 14)
P = .043 by log-rank test
0.0
0
2
4
6
8
10
12
Time (Mos)
McGonigle KF, et al. ASCO 2008. Abstract 5551.
14
16
18
20
Ovarian Cancer at First Relapse
Definition of Sensitivity
P
R 0
3
I
M
A Refractory
R
Y
T
R
E
A
T
M
E
N
T
6
12
18
24
Months
Resistant
Sensitive
“Very Sensitive”
Defined as measurable recurrence, not biochemical (CA-125) recurrence
Platinum-Resistant Recurrence
• Drugs active in platinum-resistant disease
• Single agent regimens
• Treatment to progression, unacceptable
toxicity, or clinical complete remission
with each regimen
• Sequential use of agents with goal
of palliation